Interleukin 17 (IL-17) is a family of proinflammatory cytokines consisting of six members (IL17A-F). hIL-17A is expressed by a unique lineage of CD4 T cells (Th-17) and is known to stimulate fibroblasts, endothelial, epithelial cells and macrophages to produce multiple proinflammatory mediators. These mediators include IL-1, IL-6, TNF-α, NOS-2 and chemokines, resulting in the induction of inflammation (Aggarwal, S. Journal of Biological Chemistry 278, 1910-1914 (2003)). Evidence from animal studies indicates that hIL-17A and hIL-17F are crucial for coordinating local host defense against certain bacteria and fungi in mammals. Recent studies also show that hIL-17 is actively involved in a range of pathologic conditions in humans, ranging from common asthma to several autoimmune diseases, such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, as well as allergen-specific immune responses (Kolls, J. K. Immunity 21, 467-476 (2004); Iwakura, Y. The Journal of Clinical Investigation 116, 1218-1222 (2006); Nakae, S. et al. Immunity 17, 375-387 (2002)). The signaling of hIL-17 in several cell types is mediated by binding to endogenous hIL-17 receptors (hIL-17R) that contain five receptor types, IL-17RA-IL-17RE (Aggarwal, S. Journal of Leukocyte Biology 71, 1-8 (2002)). Recently it was shown that hIL-17A signaling is mediated by a heteromeric complex containing, hIL-17RA and hIL-17RC chains (Toy, D. et al. The Journal of Immunology 177, 36-39 (2006)). Both receptors are single transmembrane proteins of ˜90 kDa, and contain conserved structural motifs (Kramer, J. M. et al. The Journal of Immunology 179, 6379-6383 (2007); Gaffen, S. L. Nat Rev Immunol 9, 556-567 (2009)). The IL-17R receptors are not homologues to any known receptors and possess unique signaling properties, which enable Th-17 cells to act as a bridge between cells of the innate and adaptive immune systems (Ely, L. K., Nat Immunol 10, 1245-1251 (2009)).
A crystal structure of hIL-17RA extra cellular domain (ECD) bound to hIL-17F has been recently published, revealing new insight into the molecular basis for IL-17 ligand and receptor interactions (Ely, L. K., Nat Immunol 10, 1245-1251 (2009)). Three main interaction sites at the binding interface were detected, Thr25-Trp31 (site 1), Leu86-Arg93 (site 2) and Cys259-Arg265 (site 3), site 2 being the most prominent interface of the complex (Ely, L. K., Nat Immunol 10, 1245-1251 (2009)). The structure showed one hIL-17RA bound to the dimeric hIL-17F cytokine, leaving the second potential receptor-binding interface free to engage to a second receptor.